Understanding the intracellular and extracellular regulatory mechanisms controlling the activation of macrophages is necessary to maximize the macrophage-mediated lysis of tumor cells. We have defined patterns of activation that will induce tumoricidal and/or suppressive functions in murine macrophages and we are characterizing the intracellular biochemical events associated with the acquisition of cytolytic activity by macrophages. The finding that tumoricidal macrophages have a depressed rate of synthesis of ribosomal RNA led to the discovery that inhibitors of RNA synthesis synergize with lymphokines in activating macrophages. These results suggest a causal relationship between decrease of RNA synthesis and macrophage activation and point to a role for inhibitors of RNA synthesis augmenting the macrophage-mediated antitumor effects. A similar experimental approach is being used to evaluate the role of protein synthesis and methylation reactions in the process of macrophage activation.